Neuroprotective effects of TNF binding protein in focal cerebral ischemia.
The effect of tumor necrosis factor binding protein (TNFbp) was studied in mice subjected to a permanent middle cerebral artery occlusion (MCAO). TNFbp is a dimeric form of the type I soluble TNF receptor linked to polyethylene glycol (TNFbp), and binds and inhibits TNF-alpha. TNFbp produced a significant reduction in the cortical infarct volume (22.6 +/- 3.5 mm3 immediately after MCAO; 25.2 +/- 2.4 mm3 1 h after MCAO) compared with vehicle-treated animals (30.3 +/- 3.7 mm3 immediately post MCAO; 31 +/- 3.7 mm3 1 h after MCAO (mean +/- S.D.) when administered intracranially up to 60 min post-occlusion. The neuroprotective effect of TNFbp was sustained in mice for 2 weeks after MCAO. DNA fragmentation at the margin of the cortical infarcts was dramatically reduced in mice treated with TNFbp whereas all control animals showed consistent and obvious DNA fragmentation 2 weeks after MCAO. TNFbp could have therapeutic value for the treatment of ischemic stroke if the problem of delivery to brain can be overcome.
Nawashiro
H
H
Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-4128, USA.
Martin
D
D
Hallenbeck
J M
JM
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000473:pathology / Q000628:therapy; D001710:Biotin; D002545:Brain Ischemia / Q000473:pathology / Q000628:therapy*; D002544:Cerebral Infarction / Q000473:pathology / Q000628:therapy; D003497:Cyclic N-Oxides; D053938:DNA Fragmentation; D003856:Deoxyuracil Nucleotides; D016166:Free Radical Scavengers / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012795:Sialoglycoproteins / Q000494:pharmacology; D013194:Staining and Labeling; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D003497:Cyclic N-Oxides; D003856:Deoxyuracil Nucleotides; D016166:Free Radical Scavengers; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D012795:Sialoglycoproteins; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; C029217:phenyl-N-tert-butylnitrone; D001710:Biotin; D010751:Phosphopyruvate Hydratase